Improvement in Safety Monitoring of Biologic Response Modifiers After the Implementation of Clinical Care Guidelines by a Specialty Pharmacy Service in an Academic Health System

BACKGROUND: Tumor necrosis factor (TNF)-alpha inhibitors and other biologic response modifiers (BRMs) are frequently used to treat a variety of inflammatory diseases. Use of these agents may increase risk of serious infections, malignancies, and other complications such as worsening symptoms of heart failure or demyelinating disease. Because of these risks, a baseline assessment and routine monitoring have been recommended, but standardized guidelines for monitoring have yet to be established. OBJECTIVES: To measure the compliance with the recommended safety monitoring in the Clinical Care Guidelines for BRMs at the University of Illinois Hospitals and Health Sciences System (UI Health). METHODS: The Clinical Care Guidelines for BRMs was developed by a committee of pharmacists, nurses, and physicians based on an assessment of published literature and medication labeling. The guidelines included recommendations for safety monitoring prior to BRM therapy, such as the tuberculosis (TB) test, Hepatitis B surface Antigen (HBsAg) test, liver function test (LFT), complete blood count (CBC), up-to-date vaccinations, risk assessment for cancer, pregnancy testing, monitoring for contraindications with concomitant medications, concomitant disease state risk assessment, and patient education. The guidelines were introduced to UI Health in February 2012 by a systemwide email and by in-services given by the health system’s Specialty Pharmacy Service. In-services were given in the clinics known to generate large numbers of BRM orders (e.g., gastroenterology and rheumatology) and at the outpatient center for infused therapies. The purpose of the in-services was to introduce providers to the guidelines and encourage their compliance. To ensure that guideline requirements were met when BRMs were ordered, a process was established to identify BRM orders, assess the orders for compliance with 4 of the safety monitoring tests from the guidelines (TB, HBsAg, LFT, and CBC), and make interventions. When necessary, Specialty Pharmacy Services coordinated with the pharmacists and other providers in the clinic to order lab tests and ensure they were completed prior to the start of therapy. Feedback was provided during the study to proactively improve compliance with the guidelines. After completion of the study, a report containing outpatient prescription orders for BRMs (abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, and tocilizumab) from August 2011 through July 2012 was generated from the electronic medical record. Retrospective analyses of completion of safety monitoring were conducted for patients administered BRM treatment. Completion rates were compared before and after implementation of guidelines in February 2012. Completion was considered to have occurred when all 4 safety monitoring tests had been conducted —TB (unless known to be positive from a previous test), HBsAg, LFT, and CBC. Completion data from August 2011 through January 2012 were before the guidelines were implemented, and data from February 2012 through July 2012 were after the guidelines. Chi square analyses were performed on completion frequencies in the patients before and after the guidelines were implemented. RESULTS: Of the 320 unique patient BRM orders evaluated in this study, 195 (61%) were generated in the Rheumatology clinic, 99 (31%) in the Gastroenterology clinic, 21 (6.5%) in the Dermatology clinic, and 5 (1.5%) in the Transplant clinic. Before the guidelines were implemented, 54 ( 31%) of 173 patient orders complied with the safety monitoring by having all 4 clinical tests performed at the appropriate time points. After guideline implementation, 88 (60%) of 147 patient orders were compliant and had all 4 clinical tests conducted, which represents a statistically significant improvement in the rate of compliance (Pearson chi square=26.43, degrees of freedom (df)=1, P  less than  0.0001). This significant improvement in compliance rates after guideline implementation was observed in both the new patient group and the patients with continuing prescription orders/treatment changes. There was also an improvement in patients whose prescriptions were dispensed by UI Health and to a lesser degree those whose prescriptions were dispensed by an outside pharmacy. When the new patient group was analyzed separately (n=92), 50 patients were treated before the guidelines were implemented, and 42 patients were treated after the guidelines were implemented. Compliance rates with safety monitoring in these 2 groups were 52% pre-implementation and 83% post-implementation, which represented a statistically significant improvement in compliance (Pearson chi square=10.03, df=1, P=0.0015). Similar results were observed in the second patient subgroup with continuing prescription orders/treatment change (n=228). A total of 123 patients were treated before the guidelines were implemented, and 105 were treated after the guidelines were implemented. Compliance rates were 23% pre-implementation compared with 50% post-implementation, which represented a statistically significant improvement in compliance (Pearson chi square=18.99, df=1, P  less than  0.0001). CONCLUSIONS: Given the widespread and long-term use of BRMs, safety monitoring and management should be an important part of a comprehensive medication management program for their use. A coordinated effort may have a significant impact on compliance with safety monitoring guidelines.

METHODS: The Clinical Care Guidelines for BRMs was developed by a committee of pharmacists, nurses, and physicians based on an assessment of published literature and medication labeling. The guidelines included recommendations for safety monitoring prior to BRM therapy, such as the tuberculosis (TB) test, Hepatitis B surface Antigen (HBsAg) test, liver function test (LFT), complete blood count (CBC), up-to-date vaccinations, risk assessment for cancer, pregnancy testing, monitoring for contraindications with concomitant medications, concomitant disease state risk assessment, and patient education. The guidelines were introduced to UI Health in February 2012 by a systemwide email and by in-services given by the health system's Specialty Pharmacy Service. In-services were given in the clinics known to generate large numbers of BRM orders (e.g., gastroenterology and rheumatology) and at the outpatient center for infused therapies. The purpose of the in-services was to introduce providers to the guidelines and encourage their compliance. To ensure that guideline requirements were met when BRMs were ordered, a process was established to identify BRM orders, assess the orders for compliance with 4 of the safety monitoring tests from the guidelines (TB, HBsAg, LFT, and CBC), and make interventions. When necessary, Specialty Pharmacy Services coordinated with the pharmacists and other providers in the clinic to order lab tests and ensure they were completed prior to the start of therapy. Feedback was provided during the study to proactively improve compliance with the guidelines. After completion of the study, a report containing outpatient prescription orders for BRMs (abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, and tocilizumab) from August 2011 through July 2012 was generated from the electronic medical record. Retrospective analyses of completion of safety monitoring were conducted for patients administered BRM treatment. Completion rates were compared before and after implementation of guidelines in February 2012. Completion was considered to have occurred when all 4 safety monitoring tests had been conducted -TB (unless known to be positive from a previous test), HBsAg, LFT, and CBC. Completion data from August 2011 through January 2012 were before the guidelines were implemented, and data from February 2012 through July 2012 were after the guidelines. Chi square analyses were performed on completion frequencies in the patients before and after the guidelines were implemented. RESULTS: Of the 320 unique patient BRM orders evaluated in this study, 195 (61%) were generated in the Rheumatology clinic, 99 (31%) in the Gastroenterology clinic, 21 (6.5%) in the Dermatology clinic, and 5 (1.5%) in the Transplant clinic. Before the guidelines were implemented, 54 ( 31%) of 173 patient orders complied with the safety monitoring by having all 4 clinical tests performed at the appropriate time points. After guideline implementation, 88 (60%) of 147 patient orders were compliant and had all 4 clinical tests conducted, which represents a statistically significant improvement in the rate of compliance (Pearson chi square = 26.43, degrees of freedom (df) = 1, P < 0.0001). This significant improvement in compliance rates after guideline implementation was observed in both the new patient group and the patients with continuing prescription orders/ treatment changes. There was also an improvement in patients whose prescriptions were dispensed by UI Health and to a lesser degree those whose prescriptions were dispensed by an outside pharmacy. When the new patient group was analyzed separately (n = 92), 50 patients were treated before the guidelines were implemented, and 42 patients were treated after the guidelines were implemented. Compliance rates with safety monitoring in these 2 groups were 52% pre-implementation and 83% post-implementation, which represented a statistically significant improvement in compliance (Pearson chi square = 10.03, df=1, P = 0.0015). Similar results were observed in the second patient subgroup with continuing prescription orders/treatment change (n = 228). A total of 123 patients were treated before the guidelines were implemented, and 105 were treated after the guidelines were implemented. Compliance rates were 23% pre-implementation compared with 50% post-implementation, which represented a statistically significant improvement in compliance (Pearson chi square = 18.99, df = 1, P < 0.0001).

Improvement in Safety Monitoring of Biologic Response Modifiers After the Implementation of Clinical Care Guidelines by a Specialty Pharmacy Service in an Academic Health System
The use of anti-TNF-alpha agents increases the risk of serious infections, including reactivation of tuberculosis (TB) and viral hepatitis B, requiring black box warnings because of significant increased risk of morbidity and mortality. 4,[9][10][11][12] TNFalpha is vital for granuloma formation, and anti-TNF-alpha agents can reactivate latent TB, a granulomatous disease. 13 The mechanism by which viral hepatitis B is reactivated with anti-TNF-alpha agents is not well understood. Abnormal liver function can also occur during treatment and may result in cholestatic disease and hepatitis. Most studies recommend discontinuing treatment if alanine aminotransferases exceeds 5 times the upper limit of normal or if jaundice develops. 11,14 Inhibition of TNF-alpha is suspected to increase the risk of malignancy, specifically lymphoma, although several metaanalyses and systemic reviews have failed to find consistent evidence supporting this conclusion. 3,9,15,16 Furthermore, new onset or worsening symptoms of congestive heart failure (CHF) have been reported as well as a decline in control of demyelinating diseases such as multiple sclerosis (MS). 4,6,10,12 Although not designated as a black box warning, the presence of conditions such as CHF or MS should prompt an evaluation of risk of use versus possible benefits, and anti-TNF-alpha agents should be used with caution.
Due to the severity of identified risks associated with anti-TNF-alpha agents, several tests are recommended before and during treatment. A test for TB is required prior to initiating treatment and annually thereafter. TB testing may include a tuberculin skin test (TST), QuantiFERON-TB Gold blood test, and/or chest x-ray to rule out infection. Treatment of the infection is indicated after a positive result from a TB test is discovered. 11 Hepatitis B viral status should be assessed prior to initiation of treatment and monitored or possibly treated in patients who are hepatitis B positive. 11,13,17,18 Liver function tests (LFT) and complete blood counts (CBC) are recommended prior to initiation and every 3 months or as frequently as the prescriber deems necessary during the course of therapy. This monitoring is performed to assess for opportunistic infections, malignancies, and liver abnormalities. 18,19 The appropriate frequency and duration of LFT and CBC monitoring for patients on long-term treatment are unclear. It is also recommended that all patients started on anti-TNF-alpha agents are up to date on routine vaccinations prior to treatment initiation, with live vaccines administered no less than 4 weeks prior to initiation. [20][21][22] Along with T-cell co-stimulation blockers, interleukin-6-receptor antagonists, and B-lymphocyte stimulators, anti-TNF-alpha agents are categorized as biologic response modifiers (BRMs). [23][24][25] Other BRMs share similar recommendations for screening and ongoing monitoring. Of the BRMs prescribed at the institution featured in this study, 93% were categorized as anti-TNF-alpha agents and, so, are the focus of this study. T umor necrosis factor (TNF)-alpha is an integral proinflammatory cytokine that is responsible for modulating intracellular pathogens and granuloma formation. 1,2 TNF-alpha is predominantly produced by macrophages and promotes the release of other inflammatory cytokines. TNFalpha is critical in immune defense against infections and contributes to the development of certain cancers. 2,3 Because of the role of TNF-alpha in inflammation, it has been identified as a key therapeutic target for treating inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis, and inflammatory bowel disease. 3 Multiple TNF-alpha agents, such as adalimumab (Humira, Abbott), etanercept (Enbrel, Amgen), infliximab (Remicade, Janssen), certolizumab (Cimzia, UCB), and golimumab (Simponi, Janssen), have been approved by the U.S. Food and Drug administration (FDA) to manage and treat several immunological conditions. [4][5][6][7][8] • Due to their immune suppressive properties, anti-TNF-alpha agents have been implicated in increasing the risk of certain types of malignancies, infections, and other complications that have resulted in boxed warnings. Serious warnings include the potential for reactivation of tuberculosis (TB) or hepatitis B and risk of liver injury and lymphoma. • There are safety recommendations in the literature for screening and monitoring with the use of these medications, including testing for TB and hepatitis B prior to initiation as well as periodic complete blood count (CBC) and liver function test (LFT) monitoring.

What is already known about this subject (continued)
• To the authors' knowledge, this is the first study that measured compliance with safety guidelines for BRMs. This study then looked at pre-and post-implementation compliance rates to see if a specialty pharmacy service had an impact on the health system's adherence to the guidelines. • The data from this retrospective study indicated that the rate of compliance with safety monitoring was improved in the entire patient sample after guidelines were implemented but were most strikingly improved in the new patients. This study indicated that safety monitoring improved dramatically when Specialty Pharmacy Services took a proactive role in managing compliance with standard guidelines. • Although the effect on outcomes is a subject of further research, this study improved the likelihood of safe use of BRMs at a health system. The Clinical Care Guidelines for BRMs was developed by a committee of pharmacists, nurses, and physicians at UI Health, based on an assessment of published literature and medication labeling. [4][5][6][7][8]11,14,17,18,[20][21][22][23][24][25][26][27] The guidelines were introduced to the health system in February 2012. The goal of the guidelines was to reinforce safety monitoring recommendations by assisting providers with clinical decisions for specific BRMs by implementing standardized monitoring and screening criteria. The guidelines provided recommendations for initiation of therapy and continuing therapy. In these guidelines, recommendations for safety monitoring prior to BRM therapy included infection risk assessment, TB tests, Hepatitis B surface Antigen (HBsAg) test, LFT, CBC, up-to-date vaccinations, risk assessment for cancer, pregnancy testing, monitoring for contraindications with concomitant medications, concomitant disease state risk assessment, and patient education. A detailed checklist for anti-TNF-alpha agents is shown in Figure 1, and the complete text of the BRM Clinical Care Guidelines is in the Appendix.

Study Objective
The objective of this study was to measure the compliance with the recommended safety monitoring in the Clinical Care Guidelines for BRMs at UI Health. A retrospective cohort of patients who were prescribed BRMs before and after implementation of the guidelines were studied by measuring the completion rates of safety monitoring.

■■ Methods Implementation of Clinical Care Guidelines
The Clinical Care Guidelines for BRMs was introduced to the health system via a systemwide email and in-services in the clinics known to generate large numbers of BRM orders, particularly gastroenterology, rheumatology, and the outpatient center for infused therapies. To ensure that guideline requirements were met when BRMs were ordered, the process outlined in the following paragraph was established to identify BRM orders, assess the orders for compliance with guidelines, and make interventions to ensure compliance when necessary. This process was performed by independent study pharmacy students under the supervision of the clinical staff pharmacist for Specialty Pharmacy Services, who also had a hybrid role providing clinical pharmacy services in the Gastroenterology clinic and had close relationships with prescribers and patients. All orders for BRMs were evaluated regardless of the origin of the prescription. Of the 320 unique patient BRM orders evaluated in this study, 195 (61%) were generated in the Rheumatology clinic, 99 (31%) in the Gastroenterology clinic, 21 (6.5%) in the Dermatology clinic, and 5 (1.5%) in the Transplant clinic. At the time of this study, only the Gastroenterology clinic and the Transplant clinic had a clinical pharmacist assigned to the service. The most common diagnoses from the electronic medical record (EMR) were rheumatoid arthritis (116, 36%); Crohn's disease (75, 23%); ankylosing spondylitis (27, 8%); ulcerative colitis (24, 8%); psoriasis (20, 6%); psoriatic arthritis (19, 6%); and sarcoidosis (17, 5%). Other diagnoses mentioned less than 2% of the time were juvenile idiopathic arthritis, Behcet's disease, adult onset Stills disease, uveitis, granulomatous disease, mixed connective tissue disease, Pityrias Rubra Pilaris, and post-transplant immunosuppression.
The Specialty Pharmacy Service identified all new BRM orders using 1 of the following approaches: (a) referral to the clinical staff pharmacist, (b) referral to the prior authorization technician for evaluation of insurance benefits, or (c) bi-weekly review of new and continuing BRM orders downloaded from the EMR. The process for assessing the BRM order for compliance with the guidelines was the same regardless of the method used to identify the order. First, utilizing the BRM Pre-Order Checklist, individual risk assessments (infection, hepatotoxicity, cancer, concomitant disease state, concomitant medications, and pregnancy) were evaluated, and the EMR was reviewed for compliance with the laboratory test requirements. If the EMR did not show complete compliance with all 4 laboratory tests (TB, HBsAg, LFT, and CBC) prior to the start of therapy or if other safety issues were identified, Specialty Pharmacy Services alerted the prescriber (usually an attending physician, resident, or fellow) by way of an internal message through the EMR or via telephone. The clinical pharmacist assigned to the specialty clinic was notified as well, and the communications were documented in the EMR. Feedback Improvement in Safety Monitoring of Biologic Response Modifiers After the Implementation of Clinical Care Guidelines by a Specialty Pharmacy Service in an Academic Health System during the study was provided on a patient-by-patient basis to proactively improve compliance with the guidelines. Specialty Pharmacy Services would then contact patients on behalf of the prescriber and coordinate with the clinical pharmacist or other providers to order the required labs and assist with any follow-up needed.
In conjunction with the evaluation of safety monitoring, the Specialty Pharmacy Service completed an insurance benefits review for patients starting on treatment with a BRM. If a prior authorization was required, it was submitted to the insurance company. Prior authorization requests were approved 96% of the time, with the only reason for denial being non-FDA approved indications, such as sarcoidosis. Once the prior authorization was approved and the patient was ready to initiate therapy, an appointment was made with the patient for education and training (for self-injectable BRMs) or for the infusion or injection (for clinic-administered BRMs). The pharmacist or the nurse in the Infusion Center were responsible for  Overall, this process improved the likelihood that BRMs were prescribed in accordance with safety measures prior to start of therapy.

Anti-TNF-Alpha Agents Pre-Order Checklist
After the initiation of BRM therapy, the guidelines required quarterly CBCs and LFTs as well as annual TB tests. For continuing patients with treatment changes, a TB test was not repeated for a patient who was previously deemed TB-positive. Instead, a chest x-ray was performed to confirm absence of disease. These patients were considered compliant with the TB test for purposes of this study. In order to assess guideline compliance with subsequent prescription refills, the pharmacist monitored each refill dispensed by the health After a recent review of (patient name, birth date) it has come to our attention that your patient may be due for one of the following tests as outlined in the clinical care guidelines for Anti-TNF medications adopted by (health care provider) in (date). This is based on the information currently available in PowerChart.

Labs that are due:
LFT -Last tested on (insert date) Needs to be completed within one month prior to treatment then every three months.

CBC -Last tested on (insert date)
Needs to be completed within one month prior to treatment then every three months.
For more details regarding these guidelines please visit: (insert link to guidelines) Also if the prescription has been suspended, discontinued, or the patient is no longer on treatment, please update the patient's medication profile to the correct status. This will ensure a decrease in the amount of unnecessary notifications sent out.
For your reference the following labs are up to date with the current guidelines:

Tuberculosis Test (TST or quantiFERON) -Last tested on (insert date)
Needs to be completed prior to starting treatment and then annually.

Hepatitis B Test (HBsAg) -(insert date)
Needs to be documented or completed prior to starting treatment.

Improvement in Safety Monitoring of Biologic Response Modifiers After the Implementation of Clinical Care Guidelines by a Specialty Pharmacy Service in an Academic Health System
infliximab, and tocilizumab) from August 2011 through June 2012 was generated from the EMR. The data contained in the report reflected 6 months of orders before implementation of the guidelines, followed by 6 months of orders after guideline implementation (including 1 month during which guidelines were introduced to the health system). Duplicate orders (more than 1 order for the same medication) or orders discontinued or inactivated prior to start of therapy were deleted from the dataset. Some patients contributed more than 1 BRM episode of use to the analysis due to dose change, medication change, or renewal; therefore, the dataset was restricted to the first episode of use per patient. The resulting list was validated by cross-referencing medication records and physician notes in the EMR to ensure that only active (dispensed by any pharmacy or clinic-administered) orders were in the dataset. Each active order was categorized as a new start (treatment-naïve patients) or continuing order/treatment change (renewal or change in BRM; see Figure 3). Once active orders were isolated, the medical record for each patient was reviewed to determine compliance with all 4 laboratory tests (TB, HBsAg, LFT, and CBC) required by the guidelines. The medication order date was compared with the date for each individual laboratory test. Orders classified as a new start were considered completely compliant if the TB test was completed within 1 year of the order date; if the HBsAg was completed any time before the order date; and if the LFT and the CBC were completed within 1 month of the order date. Orders classified as a continuation or treatment change were considered completely compliant if the TB test was completed within 1 year of the current order date; if the HBsAg was completed at any time; and if the LFT and the CBC were completed within 3 months of the current order date. For patients who had a positive TB test upon initiation of BRM therapy, repeat TB tests were not necessary with continuation or treatment change orders because any repeat test would likely be positive. Therefore, an order classified as a continuation or treatment change was considered compliant for TB even if no test was done within a year of the current order date if the initial TB test was positive, and the patient was evaluated and treated by the Infectious Disease Service. Compliance was measured as a composite rate that represented compliance with all 4 tests, since the guidelines adopted by the health system mandated all 4 lab tests. If there was clinical justification for noncompliance, such as with the CBC or the LFT, treatment was still initiated, but the patient was deemed noncompliant for purposes of this study.

Statistical Analyses
Retrospective analyses of completion of safety monitoring were conducted for patients administered BRM treatment. Completion rates were compared before and after implementation of guidelines in February 2012. Completion was considered to have occurred when all 4 safety monitoring tests system's pharmacy. If any lab tests were required at the time of a refill, the patient and prescriber were notified, and the tests were ordered. A template letter (see Figure 2) included space for the prescriber's name, patient name, patient date of birth, date the labs were completed, which labs were due, and an electronic link to the Clinical Care Guidelines. The intent of the notification letter was to create a standardized process to remind the prescriber of needed labs for continued use of the BRM. While 197 (62%) of the prescriptions for BRMs were filled at UI Health, compliance with guidelines was assessed for all orders regardless of the dispensing pharmacy. It was not possible to reliably monitor ongoing (refill) guideline compliance for prescriptions dispensed by pharmacies outside the health system, since the service had little influence on dispensing and refill coordination with no access to those records.  This improvement in compliance rates after guideline implementation was observed in the new patient group and in the patients with continuing prescription orders or treatment changes (Table 1). When the new patient group was analyzed separately (n = 92), 50 patients were treated before the guidelines were implemented, and 42 patients were treated after the guidelines were implemented. Compliance rates with safety monitoring in these 2 groups were 52% and 83%, respectively, which represented a statistically significant improvement in compliance (Pearson chi square = 10.03, df = 1, P = 0.0015). Similar results were observed in the second patient subgroup with renewed prescription orders or changes in treatment. Of the patients treated before guidelines were implemented (n = 123), 23% were compliant with safety monitoring compared with 50% (n = 105) after guidelines were implemented, which represented a statistically significant improvement in compliance (Pearson chi square = 18.99, df = 1, P < 0.0001).

Data Collection
For patients who received their prescriptions from UI Health (n = 197), 108 patients were treated before guidelines were implemented, and 89 were treated after the guidelines were implemented (Table 2). Compliance rates with safety monitoring in these 2 groups increased from 30% to 62%. A smaller but relatively comparable increase was achieved for had been conducted-TB (unless known to be positive from a previous test), HBsAg, LFT, and CBC. Completion data from August 2011 to January 2012 were results before the guidelines were implemented, and data from February 2012 to July 2012 were results after the guidelines. Chi square analyses were performed on completion frequencies in the patients before and after guidelines were implemented, using IBM SPSS v. 19 (SPSS Inc., Chicago, IL) software.

■■ Results
Percentage of compliance with the guidelines was determined for each lab test (TB, HBsAg, LFT, and CBC) in both the new order group and the group containing continuing orders and treatment changes. An improvement was seen in compliance with safety monitoring in patients treated during the 6-month period post-implementation of the guidelines, compared with compliance in the patient group treated during the 6-month period before guideline implementation (Figure 4). A total of 573 orders were initially examined, and it was determined that 320 were for unique patients. Before the guidelines were implemented, there were 173 patient orders, and 31% (n = 54) of patient orders complied with the safety monitoring by having all 4 clinical tests performed at the appropriate time points. After guideline implementation, there were 147 patient orders, and 60% (n = 88) of the patients were compliant and had all

Improvement in Safety Monitoring of Biologic Response Modifiers After the Implementation of Clinical Care Guidelines by a Specialty Pharmacy Service in an Academic Health System
patients who received their prescriptions from outside pharmacies (n = 123), with 65 patients treated before guidelines were implemented, and 58 patients treated after the guidelines were implemented. Compliance rates in these 2 groups increased from 34% to 57%.

■■ Discussion
The data from this retrospective study indicated that the rate of compliance with safety monitoring was improved after guidelines were implemented. Compliance was most strikingly improved in the new patients. This study indicated that safety monitoring improved dramatically when Specialty Pharmacy Services took a proactive role in managing compliance with standard guidelines. Prior to implementation of the Clinical Care Guidelines for BRMs in February 2012, a complete risk assessment was not consistently performed by providers in the health system. Similar findings were found in a survey of rheumatologists in the United States by Cush and Yazici (2005), who showed that rheumatologists relied primarily on clinical assessments (history, physical examination; 92%), hepatic enzymes (69%), and CBC (77%) when initiating treatment with a BRM. 28 Although specific laboratory monitoring is not currently mandated, the authors recommended that a CBC and LFT be performed every 3 months for the first 12 months for patients already started on anti-TNF-alpha agents. UI Health guidelines were implemented to provide a checklist to ensure that necessary monitoring is performed as a routine standard of care when an order for a BRM is initiated. As BRMs are more widely prescribed and their long-term use becomes more common, safety monitoring should become a standard of practice. This study represented UI Health's effort to develop and implement safety guidelines. The Clinical Care Guidelines was an interpretation of published literature and was current at the time of its release. To our knowledge, this is the first study that measured compliance with safety guidelines for BRMs. The safety risks associated with BRMs have been widely described in the literature and recommendations have been made for assessing and monitoring safe use of these agents. 17,29,30 It is widely believed that the introduction of BRMs has significantly improved patient outcomes for a variety of indicated diseases; however, the safety concerns require careful screening of candidates, especially in patients at risk for adverse events, for example, patients with certain comorbidities or patients receiving an immunomodulator along with BRMs. 29 Some have called for systems to monitor the safety and effectiveness of BRMs in everyday practice. 30 Implementation of safety guidelines for BRMs at UI Health was one such approach for monitoring safety. This approach was comprehensive and proactive and resulted in a significant increase in compliance with guidelines. What is not yet known is the relationship of guideline compliance to patient outcomes, and if improving the safe use of these biologics would result in other benefits, such as improved adherence to medication therapy. Previous studies reported on adherence with BRMs and the impact of various disease state management programs on BRM medication persistency and adherence. [31][32][33][34] One study found that specialty pharmacies reported greater refill adherence for adalimumab than retail pharmacies. 33 This was due in part to proactive refill management performed by the specialty pharmacies, such as reminder mailings, telephone calls, or emails prior to the time that a refill is needed. In a study of a rheumatoid arthritis disease therapy management program at a specialty pharmacy, patients who participated in the program had significantly greater adherence to their injectable medications compared with retail pharmacy patients. 32 Safety monitoring is an element of treatment that should be considered for any comprehensive program for BRM management. For example, it could be easily integrated with a proactive refill management program. Compliance with safety guidelines requires patients to be actively involved in their care and requires coordination between all members of the health care team. It is possible that getting patients more involved in their care and the safe use of their medications may result in better adherence and improved outcomes. The nature of the relationship needs to be studied, along with an assessment of which elements of a program have the greatest potential impact on outcomes. We propose that safety monitoring and management be a core element of any patient-centered program for BRMs.
In this study, we used the location of our Specialty Pharmacy Service within the health system to access the EMR and make interventions to ensure safety at the start of therapy. This direct access offered the opportunity to monitor and address safety concerns in a way that was not possible in a retail or traditional specialty pharmacy. This study generated questions that should be explored. Appropriateness of the guidelines as written was questioned. Monitoring safety parameters is labor intensive, and some of the tests, such as the TB test, may be more clinically important than others, such as quarterly CBCs or LFTs. There is a need for input from thought leaders on the nature, frequency, and duration of assessments with the possible development of standardized and widely accepted guidelines for safety monitoring. Further research is needed to determine the clinical relevance of the guidelines and the relationship between improved safety monitoring and clinical, economic, or humanistic outcomes. One hypothesis is that improved safety monitoring will lead to improved clinical outcomes, fewer adverse events, and lower total costs of care due to reduced utilization of health care services and more judicious use of BRMs. An additional hypothesis is that improved safety monitoring and the coordinated care offered by the health system leads to better patient satisfaction with the provided health care. These are all questions that merit further research for this class of medications.

Improvement in Safety Monitoring of Biologic Response Modifiers After the Implementation of Clinical Care Guidelines by a Specialty Pharmacy Service in an Academic Health System
There were challenges associated with implementing the Clinical Care Guidelines at UI Health. A major challenge was the lack of payment for this labor-intensive service. The analytics, monitoring, and follow-up required numerous people, including pharmacists, technicians, and pharmacy students in Specialty Pharmacy Services. For this service to be viable, justification for payment should be made and a payment source should be identified. Different models may be explored, for example, a pay-for-performance model based on the ability of the service to prevent adverse events and to save money by ensuring appropriate use. There were also challenges implementing the guidelines and the monitoring service. For example, many different prescribers were involved in ordering BRMs. It was a challenge to effectively communicate the guidelines to all providers, making frequent in-services necessary. Additionally, BRM orders originated from a variety of clinics, and referrals to Specialty Pharmacy Services were not made consistently from all of the clinics. A biweekly download of all BRM orders from the EMR provided a safety net so that orders could be reviewed on a timely basis. Not all prescription orders were dispensed by the health system pharmacy; therefore, it was difficult to monitor guidelines throughout the refill process for these orders. This may have resulted in a fragmentation of care when compared with patients who received all of their care from UI Health, including prescriptions, and who received the full potential benefit of safety monitoring. Better coordination with pharmacies outside the health system, assuming they embrace the guidelines, would allow for the same standard of care for all patients. Finally, it was a challenge to ensure complete compliance with the guidelines because not all providers agreed that the 4 lab tests should be mandatory. It was widely accepted that the TB test and the HBsAg were required prior to the start of new treatment; however, some providers considered the CBC and the LFT as recommended but not mandatory. The health system intends to review the results of this study and consider whether the guidelines should be revised.

Limitations
Several important limitations of this study should be noted. The EMR did not always have complete documentation of lab tests, especially if those tests were performed outside the health system. There was a method to scan outside lab results to the UI Health EMR; however, they were not always accurate and updated at the time of the study. If completion of the required labs could not be confirmed, the record was deemed noncompliant and may have resulted in the over-reporting of the noncompliance rate. Some BRM orders may have been excluded from this study if electronic prescribing was not utilized, which resulted in the prescription order not being captured by the EMR. For example, if a prescription was faxed directly to a specialty pharmacy or verbally ordered by telephone, and the electronic documentation of the order was inadvertently omitted, the result would be no record of it in the EMR. Therefore, these orders were not available for compliance monitoring unless a referral was made to Specialty Pharmacy Services for a review of benefits. Additionally, due to lack of access to outside pharmacy records for ongoing monitoring and refill management, only new start orders could be reliably assessed for compliance if the prescription was filled by a pharmacy outside the health system.

■■ Conclusion
Despite the limitations, this study has important implications for patients, providers, health care systems, managed care organizations, and researchers. Given the widespread and longterm use of BRMs, safety monitoring and management should be an important part of a comprehensive medication management program for BRMs. A coordinated effort can have a significant impact on compliance with safety monitoring guidelines. Research should be conducted to determine the relationship between compliance to safety guidelines and outcomes. Direct access to the EMR, prescribers, and patients facilitates a coordinated approach to ensure safe use of medications. Overall, this study increased the probability that interventions would be made to ensure safe use of BRMs at UI Health.

OBJECTIVE
To establish a uniform policy to screen patients for contraindications to initiating biologic response modifier (BRM) therapy and establish requirements for on-going monitoring for patients receiving a BRM.

POSITION STATEMENTS
• BRMs are indicated for certain chronic medical conditions and have several severe and potentially fatal adverse effects. • It is important that patients are screened for contraindications prior to the initiation of therapy and monitored closely throughout their treatment course.

1.
Prior to the initiation of a BRM, the prescriber or designee will complete the corresponding pre-order risk assessment checklist (addenda A-D).

2.
The prescriber or designee will document the completion of the checklist using the corresponding note template for that drug or drug class.

3.
The checklist is to be completed at least annually.

4.
If the medication is filled at a UIC pharmacy, the pharmacist will verify completion of the checklist prior to dispensing the medication.

5.
The Infliximab (Remicade®) Communication Form will be completed by the prescriber or designee and sent to UIC Oncology Pharmacy prior to each infliximab infusion (addendum E).